This invention is in the general field of insulin-related peptides.
Human insulin is a two-chain peptide hormone formed in the beta cells of the pancreatic islets of Langerhans. In controlling the level of blood glucose, insulin is the major fuel-regulating hormone in humans and causes a variety of physiological responses. It is believed that a certain portion of the insulin molecule is a receptor-binding region, i.e., that portion of the molecule that binds to receptor molecules on the surface of cells to initiate physiological responses. Gammeltoft, "Insulin Receptors," Physiol. Rev., 64:1321,1322 (1984). More specifically, referring to FIGS. 1 and 2, human insulin consists of an A chain of 21 amino acids SEQ ID NO. 1 and a B chain of 30 amino acids, SEQ ID NO. 2 held in three-dimensional conformation by disulfide bonds. Id. at 1352. The portion of the insulin molecule indicated by the shaded area shown in FIG. 2 is believed to be the receptor-binding region. Id. at 1343.
Diabetes mellitus Type I is a chronic and progressively degenerative illness in which the immune system of the patient produces antibodies which interfere with insulin-related function. In particular, diabetics may produce "auto," or spontaneously occurring, antibodies specific for the beta cells of the pancreatic islets, causing destruction of the cells and thus of the insulin-producing capacity of the patient. Darnell, et al., Molecular Cell Biology. Scientific American Books. New York: 1986. In most cases, insulin therapy, consisting of injections of insulin into the patient's bloodstream, can overcome the problem. However, the development of antibodies to insulin in the patient being treated is an accepted consequence of the therapy. Palmer et al., Science, 222:1337 (1983). Human insulin antibodies, or insulin antibodies from other animals arising in an immunological response to insulin injection, are believed to recognize a binding site on the insulin molecule that overlaps the insulin receptor-binding site, for a truncated insulin analogue, desoctapeptide-insulin (B23-30 desoctainsulin), is substantially reduced in both biological and immunologic activity compared to naturally occuring insulin. Bromer et al., Biochim. Biophys. Acta, 133:219 (1967).
Recently, the presence of spontaneously occurring insulin antibodies (or insulin "auto"antibodies) has been reported in the serum of at least 18% of newly diagnosed Type I diabetic patients before they had received any insulin therapy. Palmer et al., Science, 222:1337 (1983). This result has been confirmed by a number of different groups. Arslanian et al., Diabetes, 34:926 (1985); Srikanta et al., Diabetes, 35:139 (1985); Soeldner et al., N.E. J. Med., 313:893 (1985); and Dean et al., Diabetalogia, 29:339 (1986).